The folic acid antimetabolites aminopterin and amethopterin (also known as 10-methylaminopterin or methotrexate) are antineoplastic agents. These compounds inhibit enzymatic conversions involving metabolic derivatives of folic acid. Amethopterin, for example, inhibits dihydrofolate reductase (DHFR), an enzyme necessary for the regeneration of tetrahydrofolate from dihydrofolate which is formed during the conversion of 2-deoxyuridylate to thymidylate by the enzyme thymidylate synthetase.
Other derivatives of folic acid and aminopterin have been synthesized and tested as antimetabolites. Among these are compounds in which a methylene or methylidine group occupies a position in the molecule normally occupied by an amino or nitrilo group, respectively. These derivatives have varying degrees of antimetabolic activity. 10-Deazaaminopterin is highly active [(Sirotnak, et al., Cancer Treat. Rep., 62:1047 (1978)] and 5-deazaaminopterin has activity similar to that of amethopterin [(Tayler, et al., J. Org, Chem., 48:4842 (1983)]. 8,10-Dideazaaminopterin is reported to be antimetabolically active (U.S. Pat. No. 4,460,591) and 5,8,10-trideazaaminopterin exhibits activity against mouse L1210 leukemia [(Yan, et al., J, Heterocycl, Chem., 16:541 (1979)]. 10-Deazafolic acid, on the other hand, shows no significant activity (Struck, et al., J. Med. Chem., 14:693(1971) and 5-deazafolic acid is only weakly cytotoxic. 8,10-Dideazafolic acid is only marginally effective as a dihydrofolate reductase inhibitor [(DeGraw, et al., "Chemistry and Biology of Pteridines", Elsevier, 229 (1979)] and 5,8,10-trideazafolic acid also shows only marginal activity against mouse L1210 leukemia [(Oatis, et al., J. Med. Chem., 20:1393 (1977)]. 5,10-Dideazaaminopterin and 5,10-dideaza-5,6,7,8-tetrahydroaminopterin, and the corresponding 5,10-dideazafolic acid derivatives are reported by Taylor, et al., J, Med. Chem., 28, No. 7:914 (1985).
Additional derivatives of folic acid and aminopterin include: 10-oxafolic acid and 7,8-dihydro-10-oxafolic acid which are not effective inhibitors of DCM resistant Lactobacillus casei dihydrofolate reductase; 10-oxaaminopterin and 7,8-dihydro-10-thiofolic acid, which are potent DHFR inhibitors [(Nair, et al., J. Med. Chem., 19, No. 6:825 (1976)]; 10-thiafolic acid, a moderate DHFR inhibitor; and a very potent dihydrofolate reductase inhibitor, 10-thiaaminopterin [(Kim, et al., J. Med. Chem. 18, No. 8:776 (1975)].
The present invention provides novel "open-chain" folic acid derivatives, hereinafter referred to as pyrimidinyl-glutamic acid derivatives, intermediates for the preparation, pharmaceutical compositions, and their use for the inhibition of dihydrofolate reductase and the treatment of susceptible neoplasms in mammals.